Cardiac disease is one of the leading causes of death in the United States. The incidence of cardiac disease increases rapidly with advancing age.
It is well appreciated that the mammalian adult heart undergoes a number of changes with advancing age (1-3). Recent studies indicate that one of the key transcription factors in muscle and other tissues, serum response factor (SRF), is implicated in the regulation of cardiac genes during development and during adult aging (4-7). SRF is a member of the MADS (MCM1, Agamous, Deficiens, SRF) family of transcription factors that regulates a number of immediate-early and muscle-specific genes, and also serves to regulate cell proliferation, cell size, and cell survival (4-11). SRF forms dimers and recruits SRF cofactors or SRF binding proteins when it binds to the serum response element (SRE), which is located in the promoter region of each of its target genes (8-12). SRF is highly expressed in the heart during embryonic and early postnatal development, and it is mildly increased by approximately 20% from post-maturational adulthood to senescence (4-7, 12). The mRNA levels of a number of SRF target genes, including atrial natriuretic factor (ANF), alpha-myosin heavy chain (α-MHC), and sarcoplasmic reticular calcium ATPase (SERCA2), have also been reported to undergo changes during early postnatal cardiac development and during senescence (4-7, 12-14). In a transgenic mouse model in which the human SRF gene was mildly overexpressed in the heart, cardiac changes resembling those that have been observed during adult aging in terms of myocardial function, morphology, and gene expression were observed in young adulthood (7). The mildly increased cardiac-specific SRF expression apparently up-regulates some SRF target genes while it down-regulates others in the heart (7). This bidirectional pattern of altered gene expression following mild SRF up-regulation suggests that possibly other transcription regulators, including perhaps certain SRF cofactors, may pose either positive and/or negative modulatory effects on the activation of SRF target genes (7, 14-18). These other proteins and/or cofactors may also modulate SRF in its ability to regulate cell growth and proliferation (4-11).
SRF has been reported to exhibit functional interactions with a number of SRF cofactors and/or binding proteins in the regulation of SRF target genes (15-17). These interactions likely modulate SRF function and may also enable SRF to mediate tissue-specific regulation at different developmental stages (18-20). To date, a number of SRF cofactors, including the TCF family of proteins, the SAP protein myocardin, Nkx 2.5, and Hop, have been identified, and their various functions in cardiac development have been investigated (20-23). Fewer studies have reported on the role of SRF cofactors in the regulation of cardiac genes during adult aging and senescence.
New tools to understand the biology of cardiac disease and the changes in the heart that occur with advancing age are needed. Materials useful to screen for genetic susceptibility to heart conditions are needed. Materials useful to reverse or halt some of the changes in the heart that occur in a disease or with advancing age are needed.
Cancer is the second leading cause of death in the United States. New tools and materials to inhibit cancer cell proliferation, treat cancer, and understand cancer biology are also needed.